Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism spectrum disorder with an estimated frequency of about 1:4000-5000, affecting all racial and ethnic groups worldwide. Enormous progress in basic and translational FXS research has identified many neuronal targets and allowed early clinical trials of new treatments targeted to the underlying disease. A number of these agents have shown signal for benefit in open-label and early phase trials, but it has been challenging to meet primary behavioral outcomes in larger phase 2b and 3 trials, due to multiple complex issues including dosing age of subjects, length of treatment, placebo effects, and primary outcome off target for drug effect. A significant problem has been poor availability of biomarkers and well-validated cognitive and other objective outcome measures that do not rely on parent report. Further, very long-term treatment over years, a time frame over which placebo controls are not possible, will be necessary to show changes in the trajectory of disease. In order to know whether the disease trajectory has been changed, it will be CRITICAL to have detailed longitudinal phenotyping including cognitive, adaptive, language, motor, behavioral, social, and quality of life on a large cohort of individuals with FXS, in order to define the naturl history of the disease for future comparison in long-term intervention studies. The FORWARD longitudinal database tracks health, behavior and social issues including 3 standardized measures of behavior and social function in a large cohort of individuals with FXS but lacks good consistent cognitive and adaptive data. Given the infrastructure already present, the FORWARD project is the only currently plausible place to collect the necessary detailed longitudinal phenotyping. Thus, through this application, focused on both enhanced measurement and participation, we plan to collaborate with other Component C sites to enhance the cohort size in which we will collect a comprehensive core battery of outcome measures yearly for a minimum of 3 years to begin to define the longitudinal trajectory of all aspects of the FXS phenotype (Aim 1). At the Denver site we will also collect pilot data longitudinally for new outcome measures addressing areas of need in FXS (Aim 2): a direct measure of social interaction usable across the lifespan (Autism Screening Instrument for Educational Planning-Interaction), efficient assessment of adaptive functioning (Pediatric Evaluation of Disability Inventory-Computer Adaptive Test), detailed tracking of ADHD symptoms across the lifespan (Conners ADHD rating scales), and an efficient battery evaluating motor skills (Fragile X Short Motor Battery). Finally, we will implement plans to improve collection of this data from underrepresented minorities and adults with FXS through outreach activities and collaboration with the Colorado Dept of Health (Aim 3). Analysis plans for data will be reviewed and modified by experts in FXS outcomes research and CDC partners. Results will be disseminated to stakeholders including the FXCRC, NFXF, FXS Community Support Networks, FXS families, other researchers and CDC project partners.